Program Description/Abstract Metabolic reprogramming is a fundamental process underlying the growth of cancer cells and activated lymphocytes. These rapidly dividing cells markedly upregulate aerobic glycolysis (Warburg metabolism) and also reprogram mitochondrial oxidative phosphorylation (OXPHOS) to support the energy and growth demands. Moreover, mTOR signaling is a central regulator of anabolic metabolism in cancer cells and lymphocytes. While Warburg and mitochondrial metabolism and mTOR signaling are being actively studied, we are just beginning to appreciate the involvement of other biosynthetic programs such as de novo lipid synthesis (lipogenesis). Emerging evidence highlights that cancer immunotherapy is a powerful tool to combat cancers, but immune tolerance mediated by immunosuppressive regulatory T cells (Tregs) represents a major obstacle for effective anti-tumor immunity. Although mTOR was generally considered a crucial negative regulator of Tregs, our genetic studies have revealed that mTORC1 is a pivotal positive determinant of Treg function by linking immune signals to the lipogenic program. In our preliminary studies, disruption of the lipogenic program in Tregs rendered the mice to reject tumor cells but did not cause obvious autoimmune disorders under steady state. We hypothesize that lipogenic program contributes to Treg suppressive activity in the tumor microenvironment, which could represent a novel target for cancer immunotherapy. We will test this hypothesis by establishing the roles of Treg lipogenic programs in tumor immunity, and determining the metabolic and signaling basis whereby lipogenesis programs Treg functions. We predict these studies will establish a new paradigm on our understanding of lipogenic program in Tregs and how this impinges upon tumor immunity. Insights gained from this project will likely lead to innovative strategies on cancer immunotherapy by capitalizing on metabolic reprogramming of Tregs.